Association Between Topical Calcineurin Inhibitor Use and Risk of Cancer, Including Lymphoma, Keratinocyte Carcinoma, and Melanoma: A Systematic Review and Meta-analysis

Abstract

Importance: Topical calcineurin inhibitors (TCIs) are commonly used as second-line treatment for atopic dermatitis. In 2006, the US Food and Drug Administration issued a black box warning against TCI use, citing data from case reports and animal studies indicating a potential risk of cancer.

Objective: To evaluate the association between TCI use and risk of malignant neoplasms compared with nonactive and active comparator groups.

Data sources: Electronic searches were conducted in MEDLINE via Ovid, Embase via Ovid, and Web of Science from database inception to August 21, 2020.

Study selection: Observational studies investigating the association between treatment with TCIs (ie, tacrolimus and pimecrolimus) and the development of cancer with nonactive or active comparators were included. The population of interest was not limited to any specific disease state, age, or sex. All articles were assessed independently and in duplicate by 2 reviewers. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 2464 nonduplicate records retrieved from the search, 11 studies met the inclusion criteria.

Data extraction and synthesis: Data extraction was conducted independently by 2 reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Random-effects meta-analyses were used to derive pooled relative risk (RR) estimates. Data were analyzed from July 25 to October 25, 2020.

Main outcomes and measures: Risk of cancer overall and risk of specific cancer types (lymphoma, melanoma, and keratinocyte carcinoma).

Results: Eight unique cohort studies (408 366 treated participants [55.1% female], 1 764 313 nonactive comparator controls, and 1 067 280 controls using topical corticosteroids) and 3 unique case-control studies (3898 cases [55.0% male] and 14 026 cancer-free controls [52.4% male]) were included. There was no association between TCI use and cancer overall compared with nonactive comparators (RR, 1.03; 95% CI, 0.92-1.16). Lymphoma risk was elevated with TCI use with both nonactive (RR, 1.86; 95% CI, 1.39-2.49) and topical corticosteroid comparators (RR, 1.35; 95% CI, 1.13-1.61). No significant association was found between TCI use and increased skin cancer (melanoma and keratinocyte carcinoma).

Conclusions and relevance: The findings of this systematic review and meta-analysis suggest an association between TCI use and risk of lymphoma but not other cancers. Combined with the low absolute risk of lymphoma, the potential increased risk attributable to TCI use for any individual patient is likely very small.

Figure 1.. Study Selection Methods

TCIs indicates topical calcineurin inhibitors.

Figure 2.. Risk of Any Cancer With Topical Calcineurin Inhibitor (TCI) Treatment and Nonactive Comparator in Cohort Studies

Relative risks (RRs) were calculated using random-effects inverse variance method. Marker size indicates weight; diamond size indicates heterogeneity. PIM indicates pimecrolimus; TAC, tacrolimus.

Figure 3.. Risk of Lymphoma With Topical Calcineurin Inhibitor (TCI) Treatment in Cohort Studies

Results are stratified by B-cell lymphoma (BCL) and T-cell lymphoma (TCL) (A) and participant age (B). Relative risks (RRs) were calculated using random-effects inverse variance method. Marker size indicates weight; diamond size indicates heterogeneity. PIM indicates pimecrolimus; TAC, tacrolimus; TCS, topical corticosteroid. ^aOther lymphoid and histiocytic tissue. ^bLymphosarcoma and reticulosarcoma.

Figure 4.. Risk of Melanoma and Keratinocyte Carcinoma After Topical Calcineurin Inhibitor (TCI) Treatment

Relative risks (RRs) were calculated using random-effects inverse variance method. Marker size indicates weight; diamond size indicates heterogeneity. PIM indicates pimecrolimus; TAC, tacrolimus; TCS, topical corticosteroid. ^aIndicates melanoma. ^bIndicates keratinocyte carcinoma.